This research proposal is directed toward understanding the mechanisms of oligodendrocyte apoptosis in response to p75 activation by NGF. Recently, NGF has been shown to mediate cell death in several types, but the mechanisms by which this occurs has not been established. The TNF receptor and Fas are molecules structurally related to p75. When activated by their respective ligands, they too can cause certain cells to undergo apoptosis. Several mechanisms by which apoptosis occurs via TNF and Fas antigen have been well studied. These include an involvement of ICE and ICE-like proteases and activation of the JNK pathway. In addition, TNFR-and FAS- interacting molecules implicated in mediating cell death have been identified and shown to interact with a "death domain" found in the intracellular portions of these receptors. p75 also possesses this motif. Additionally, the expression of p75 alone is not sufficient to induce apoptosis, as Schwann cells express high levels of p75 but do not undergo cell death in the presence of NGF. The working hypothesis of this proposal is that (1) NGF activation of the p75 receptor leads to sustained c-Jun activation and/or ICE and ICE-like protease activation, either of which can promote cell death; and (2) novel molecules that are involved in mediating an apoptotic signal may exist and interact with the death domain of p75.